The goal of this project is to establish that protein kinase D (PKD) is a major regulator of bone formation in vivo and that attenuation of PKD activity leads to age-related osteopenia. Our published and preliminary data, as well as that of others, indicated that PKD activity is required for the in vitro differentiation and mineralizationof osteoblasts in response to bone morphogenetic proteins (BMPs) and that in aged animals there is in vitro and in vivo resistance to the bone forming actions of BMP-7. The recent availability of mouse models with deficiency of PKD1 or PKD2 catalytic activity has allowed us to obtain preliminary in vivo data indicating that the bone mineral density of pubertal PKD1 and PKD2 deficient mice is significantly reduced compared to their age- and gender-matched littermates. We will now test whether native bone of PKD1 and PKD2 deficient mice show diminished bone mineral density, impaired bone architecture, and age-related osteopenia, compared to wild-type controls throughout the life span. We will also determine whether the reduction in bone mineral density in these PKD deficient mice is due to alternations in bone formation or in bone resorption or both. This will be accomplished using cultured osteoprogenitor cells from these PKD1 and PKD2 deficient mice. We will utilize DEXA and CT scanning in young, middle aged and old mice to determine whether: 1) Native bone of younger PKD deficient mice exhibits attenuated mineral content and density as is observed in older wild type mice, and 2) BMP-7 induced ectopic bone, whose formation is attenuated in older mice, shows reduced activation of PKD in the old wild type mice, and whether young mice deficient in PKD catalytic activity exhibit attenuated bone formation similar to that seen in older wild type mice. Successful outcomes will provide proof of principal that PKD is a critical determinant of bone remodeling in the intact animal setting, and that age related reduction in the ability of growth factors to activate PKD in vivo has major consequences for age-related osteoporosis.